Shahinuzzaman Md, Khetan Jawahar, Barua Dipak
Chemical and Biochemical Engineering, Missouri University of Science and Technology, Rolla, MO 65409, USA.
R Soc Open Sci. 2018 Sep 26;5(9):180190. doi: 10.1098/rsos.180190. eCollection 2018 Sep.
Aggregation of cell surface receptor proteins by multivalent antigens is an essential early step for immune cell signalling. A number of experimental and modelling studies in the past have investigated multivalent ligand-mediated aggregation of IgE receptors (FcRI) in the plasma membrane of mast cells. However, understanding of the mechanisms of FcRI aggregation remains incomplete. Experimental reports indicate that FcRI forms relatively small and finite-sized clusters when stimulated by a multivalent ligand. By contrast, modelling studies have shown that receptor cross-linking by a trivalent ligand may lead to the formation of large receptor superaggregates that may potentially give rise to hyperactive cellular responses. In this work, we have developed a Brownian dynamics-based spatio-temporal model to analyse FcRI aggregation by a trivalent antigen. Unlike the existing models, which implemented non-spatial simulation approaches, our model explicitly accounts for the coarse-grained site-specific features of the multivalent species (molecules and complexes). The model incorporates membrane diffusion, steric collisions and sub-nanometre-scale site-specific interaction of the time-evolving species of arbitrary structures. Using the model, we investigated temporal evolution of the species and their diffusivities. Consistent with a recent experimental report, our model predicted sharp decay in species mobility in the plasma membrane in response receptor cross-linking by a multivalent antigen. We show that, due to such decay in the species mobility, post-stimulation receptor aggregation may become self-limiting. Our analysis reveals a potential regulatory mechanism suppressing hyperactivation of immune cells in response to multivalent antigens.
多价抗原使细胞表面受体蛋白聚集是免疫细胞信号传导必不可少的早期步骤。过去，许多实验和建模研究调查了多价配体介导的肥大细胞质膜中IgE受体（FcRI）的聚集。然而，对FcRI聚集机制的理解仍不完整。实验报告表明，FcRI在受到多价配体刺激时会形成相对较小且大小有限的簇。相比之下，建模研究表明，三价配体引起的受体交联可能导致形成大型受体超级聚集体，这可能会引发细胞过度活跃反应。在这项工作中，我们开发了一个基于布朗动力学的时空模型来分析三价抗原引起的FcRI聚集。与现有的采用非空间模拟方法的模型不同，我们的模型明确考虑了多价物种（分子和复合物）的粗粒度位点特异性特征。该模型纳入了膜扩散、空间碰撞以及任意结构的随时间演化的物种的亚纳米尺度位点特异性相互作用。利用该模型，我们研究了物种及其扩散系数的时间演化。与最近的一份实验报告一致，我们的模型预测，由于多价抗原使受体交联，质膜中物种的迁移率会急剧下降。我们表明，由于物种迁移率的这种下降，刺激后受体聚集可能会自我限制。我们的分析揭示了一种潜在的调节机制，可抑制免疫细胞对多价抗原的过度激活。
